1. Transfusion Reactions
Barbara A. O’Malley, M.D.
Associate Director of Transfusion Medicine
Harper University Hospital
Detroit Medical Center

2. Complications of transfusion
Acute hemolytic transfusion reaction= rapid destruction of red cells immediately or within 24 hours of transfusion
Most common cause is clerical error: misidentification of the patient
Hypotension, shock, consumptive coagulopathy & acute renal failure
High mortality rate

3. Acute hemolytic transfusion reaction
Rate 1 in 12,000 to 1 in 35,000 reactions per units transfused
Fatal 1 in 100,000 to 1 in 600,000 units transfused
74% of all fatalities are due to ABO incompatibility
Reported rates may underestimate actual occurrences

4. Conditions that destroy donor red cells
Naturally occurring antibodies (ABO)
Stimulated alloantibodies (anti-K, Jka)
Autoantibodies
Drug-induced antibodies
Bacterial contamination
Mechanical trauma associated with infusion
Thermal trauma (heat or cold)
Reconstitution of red blood cells with hypotonic solutions
Equipment that damages blood cells extracorporeally

5. Conditions that destroy recipient red cells
ABO incompatible plasma, cryoprecipitate, or plasma-derived products
(including platelet products which contain plasma)
Infusion of large amounts of hypotonic solutions
Mechanical trauma
(mechanical heart valves, microangiopathic syndromes)

6. Signs & Symptoms of Acute Hemolytic TR
Fever
Chills/ rigors
Anxiety, feeling of dread
Facial flushing
Chest pain
Abdominal pain
Back & flank pain
Nausea
Vomiting
Diarrhea
Dyspnea
Hypotension
Hemoglobinuria
Hemoglobinemia
Pallor
Icterus
Oliguria/anuria
Pain at transfusion site
Diffuse bleeding
Jaundice

7. Management of AHTR Stop transfusion & maintain venous access
Rapid assessment of pt & requirements for basic & advanced support
Notify transfusion service, collect transfused units & tubing and return to BB
Reconfirm identity of blood units & pt
Collect appropriate patient blood specimens
Supportive approaches

8. Management of AHTR
Maintain IV fluids at 3000 ml/M2/day with administration of sodium bicarbonate to keep pH >7.0
Diuretics:
Mannitol (20%) 100ml/ M2 given over min, then 30 ml/M2/hr for next 12 hrs.
Furosemide : Adults: mg. / Infants & children: 1-2 mg/kg up to an adult dose
Dopamine, low dose: 1-5 mcg/kg/min
Replacement of coagulation factors and platelets
Heparin (controversial in severe DIC) enhances anti-thrombin III

9. Additional Transfusion Reactions
Delayed hemolytic TR (DHTR)
Febrile nonhemolytic (FNHTR)
Uncomplicated allergic (urticaria)
Anaphylactoid
Anaphylactic (ie. IgA-deficiency)
TRALI (Transfusion-Related Acute Lung Injury)
TACO (Transfusion-Associated Circulatory overload)
Septic Reaction
Post-transfusion (profound thrombocytopenia purpura wks post-transfusion, rare)
Iron overload

10. Delayed Hemolytic Transfusion Reactions
Antibody not detected at the time of XM
Rapid secondary boost in antibody level after transfusion: Anamnestic response
1:2500 to 1:6000 transfusions
Typically cause jaundice at day 5 onwards
May cause hemoglobinuria
Renal failure very rare
Probably under-reported

11. Febrile Non-Hemolytic Transfusion Reaction
Due to cytokines/bioactive proteins in donor plasma or
Released after WBC antibody in recipient reacts with WBC antigen in product.
Stop transfusion to clinically assess:
Consider acute hemolytic, and bacterial sepsis as part of differential
Report TR to lab, send bag and samples to lab for work up
Treat symptoms with antipyretic (acetaminophen)

12. Febrile nonhemolytic reactions
Frequent 1: 650 – 1000*
Mainly occur with red cells and platelets
Usually start within 30 minutes
Patient feels cold, shaking, rigors
Temperature rises
Diastolic BP rises
Infected blood should also be considered when this type of reaction occurs
*Transfusion 2004; 44: 1-4

13. Allergic reaction Frequent 1 in 250 Usually mild, self-limited
Urticaria
Antihistamine prevents
Patient is allergic to something in the donor (foodstuff, medication, protein) or or in the pack (Latex)
May need to use washed products
If Donor is atopic
Should not be allowed to donate

14. Anaphylactic reaction
Severe anaphylaxis
Bronchospasm, shock
1:20,000 to 1: 50,000
Usually seen in IgA deficient subjects
They form antibodies to donor IgA
They must receive IgA deficient products

15. TRALI: Transfusion Related Acute Lung Injury
Severe and potentially fatal reaction to transfusion
Associated with infused granulocyte
antibodies and anti-HLA antibodies from donor
Usually donor is multiparous female

16. TRALI
Chills, fever, dyspnea, non-productive cough, hypotension, 4-6 hours after transfusion
Causes severe respiratory distress and
hypoxemia
CXR shows bilateral nodular infiltrates
with no cardiac enlargement
Pulmonary wedge pressure is normal

17. TRALI Symptoms clear in 24 hrs CXR clears in 4 days
Estimated frequency 1: 5,000 transfusions
Underdiagnosed, often occurs in
patients with other reasons for ARDS
and is overlooked

18. TRALI
Donor antibodies activate Pt’s WBC’s which cause damage to blood vessels in lung tissue
Then fluids and proteins leak into alveolar space/interstitium
Mechanism similar to ARDS

19. TRALI Management Steroids Aggressive ventilatory support
Hemodynamic support

20. TRALI
Prevention:
Hemovigilance: Reporting reactions in order to screen involved donor for HLA and neutrophil antibodies
UK: all male donor plasma
ARC: moving in the direction of all male donor plasma

21. TACO: Transfusion-Associated Circulatory Overload
Cause:
Iatrogenic – physician induced rxn
Fluid(s) administered faster than Pt circulation can accommodate volume load
Some at risk types of pt.’s: congestive heart failure, renal failure, hepatic cirrhosis, normovolemic anemia

22. TACO Signs & Symptoms Cough Dyspnea Pulmonary congestion Headache
Hypertension
Tachycardia
Distended neck veins

23. TACO
Management:
Place Pt in upright position, if possible, with feet in dependent position
Diuretics
Oxygen
Morphine (if necessary)

24. TACO
Prevention
Adjust transfusion flow rate based on Pt size and clinical status
Consider dividing unit(s) into smaller aliquot(s) to better space apart blood component(s) pace of transfusion

25. Septic Reaction Signs & Symptoms: Cause: Rapid onset of chills & fever
Vomiting, Diarrhea
Profound hypotension, Shock
Cause:
Transfusion of bacterially contaminated blood components
Common problem for platelet concentrates stored at room temp.

26. Septic Reaction Management Obtain blood cultures from Pt
Return blood component bag(s) to blood bank for further laboratory work-up
Treat septicemia with antibiotics
Treat shock with fluids & vasopressors

27. Septic Reaction Prevention
Collect, process, store, transport, and transfuse blood components according to contemporary standards of practice (e.g. for FDA standards adhere to cGMP’s – current good manufacturing practices – found in Code of Federal Regulations)
Transfuse blood components within 1 to 2 hrs – do not exceed 4 hrs

28. Complications of Transfusion
Immunomodulation
Post-operative infections
Transfusion transmitted infections
Graft vs host disease

29. Transfusion Associated Graft Vs Host Disease (TA-GVHD)
Symptoms and signs:
Skin rash trunk to extremities day 4 to 30
Fever day 4 to 23
Leukopenia day 11 to 30
Hepatitis
Secondary bacterial / fungal infections
Death day 12 to 65

30. TA-GVHD Cause / culprit: transfused lymphocytes
May occur in immunosuppressed
or immunocompetent persons
In the immunosuppressed, leukemia and BMT patients are most at risk
In immunocompetent persons:
Donor is a homozygote for HLA haplotype carried by patient

31. TA-GVHD In the non-immunosuppressed:
Areas with high rate of HLA homozygosity
Japan ( 1 in 400 )
Open heart surgery patients
Cases where fresher blood is used
Those receiving blood from close family members (directed donations)

32. TA-GVHD Often missed or misdiagnosed
Occurs in patients with other pathology
Preventable by irradiation of cellular blood products: prevents the transfused lymphocytes (Graft) from attacking recipient (Host)

33. TA-GVHD
Gamma irradiation virtually 100% effective in preventing transfusion-associated GVHD
Irradiate all cellular products transfused to pts at risk
Crosslinks DNA, prevents proliferation of lymphocytes
25Gy to midplane of the blood container,
min 15Gy to any point of the irradiated field;
max dose not to exceed 50Gy

34. TA-GVHD Clear risk Congenital immunodeficiency Hodgkin’s disease
CLL treated with fludarabine
Newborns with erythroblastosis fetalis
Directed donations (relatives)
Recipients of HLA matched platelets
Probable risk
Other hematologic malignancies
Solid tumors treated with cytotoxic agents
Genetically homogeneous populations
Premature and possibly full-term neonates
No defined risk
AIDS pts
Immunosuppressive medications

35. Laboratory Investigation of Transfusion Reactions
Sharon Lowry, MT(ASCP)SBB
University of Michigan Hospitals
October 24, 2008 35

36. Acute
Sepsis
TRALI
Anaphy-lactic
Delayed 36

37. Acute Reaction 1 Stop transfusion; keep line open - saline 2
Contact physician for instructions 3
Perform clerical check of patient and blood 4
Notify blood bank 5
Return blood unit, IV solution and tubing 6
Collect post-transfusion sample STAT 7
Complete transfusion reaction form 37

38. Standard Investigation
Clerical
Check
Visual Check
ABO
Post
Post DAT 38

39. Why Do a Clerical Check? Detect labeling errors
Detect patient identification errors
Treat patient for ABO incompatibilities
Prevent companion errors with another patient or another blood unit 39

40. Clerical Check - Bedside
At the bedside compare
Patient identification
Labels on blood unit 40

41. Clerical Check – Blood Bank
Compare post-transfusion sample/record
Pre-transfusion sample
Pre-transfusion test results
Blood unit labels
Inspect blood unit for color change
Confirm IV fluid is saline 41

42. Destruction of 5mL of red cells may be visible
Why Do a Visual Check?
Hemolysis in patient plasma may be a sign of an acute hemolytic reaction
Antibodies bind to antigens on transfused RBCs
Complement system activated
RBCs are destroyed
Free hemoglobin is released into the plasma
Destruction of 5mL of red cells may be visible 42

43. Visual Check for Hemolysis
Observe pink or red color in plasma of post-transfusion sample
Compare with pre-transfusion sample 43

44. Visual Check Problems Hemolysis observed in plasma may be
Myoglobinemia in trauma
Hemolysis in the donor unit
Underlying condition: AIHA, G6PD
Traumatic draw
Collect second sample if hemolysis present 44

45. Repeat Rh for additional confirmation
Why Repeat the ABO?
Sample
Wrong label
Wrong patient
Lab
Double sample labels
Specimen mix up
Switched blood tags
Recipient ID
Wrong unit
Repeat Rh for additional confirmation 45

46. Post ABO Result Compare to pre-transfusion ABO
Repeat pre-transfuion ABO if different
Explain mixed field agglutination 46

47. WBITs Discovered by transfusion reaction
Wrong Blood In Tube
Discovered by transfusion reaction
Not discovered if companion sample is same blood type
Missed during pre-transfusion testing when patient has no historical record 47

48. CAP TRM.30575 Among the risk reduction options are:
Does the facility have a plan to implement a system to reduce the risk of mistransfusion for non-emergent red cell transfusions?
Among the risk reduction options are:
Documenting the ABO group of the intended recipient on a second sample collected at a separate phlebotomy
Utilizing a mechanical barrier system or an electronic identification verification system that ensures that the patient from whom the pretransfusion specimen was collected is the same patient who is about to be transfused.
The use of a second manual banding system, while acceptable, is probably not as effective as the above two options.   48

49. Never should have happened
Never Events
Never should have happened
Incompatible blood transfusions are preventable
Medicare and other insurers will stop paying for added costs of treatment
Patients cannot be charged for error costs 49

50. Why Do a DAT? Detect incompatibility
Patient antibodies coat transfused RBCs
Undetected antibodies
Donor antibodies coat patient RBC antigens 50

51. Key DAT Points Saline control Centrifugation
Wash EDTA cells thoroughly
2-5% cell suspension
Polyspecific, IgG, Complement AHG
Saline control
Centrifugation
Grade/record agglutination immediately
Incubate complement, if directed
IgG and Complement check cells
If post DAT positive, perform pre DAT 51

52. DAT Best Practice No delays start to finish!
Fresh cell suspension prevents IgG disassociation
Immediate centrifuging/reading prevents weakened agglutination 52

53. Post DAT Problems Positive before transfusion
Invalid due to spontaneous agglutination
Negative if transfused red cells are destroyed
Negative with low levels of attached globulins 53

54. Positive Investigation
Blood Bank
Hematology
Urinalysis
Chemistry 54

55. Urinalysis Red or dark urine is observed Visual check shows hemolysis
Additional test for intravascular hemolysis 55

56. Urinalysis Results If blood is detected, exam microscopically
Hemoglobinuria= RBC absent (Hemolysis)
Hematuria = RBC present (R/O hemolysis)
Compare to pretransfusion results 56

57. Further Testing: Blood Bank
Post-transfusion DAT positive:
Elution
Include ABO cells if indicated
Antibody screen pre and post
AHG crossmatch pre and post
Antibody studies
Antibody enhancement studies 57

58. Acute Reaction Antibodies
ABO
Kidd K
Fya Rh
Others 58

59. Other Lab Testing LDH increased Bilirubin increased (5-7 hours)
Haptoglobin decreased
CBC, platelet count
Coagulation studies for DIC
BUN, creatinine, urine output 59

60. Other Investigations
Sepsis
TRALI
Anaphy-lactic
Delayed 60

61. Sepsis Brown/purple/frothiness/bubbles observed in unit
Gram’s stain and culture blood unit and patient
Problems:
Little or no blood left in bag
Contamination during sample collection
Gram negative organisms (Yersinia enterocolitica
Coagulase- negative Staphylococcus
Others 61

62. TRALI Test pre-transfusion and post-transfusion samples
BNP not increased
CBC may show decreased WBCs
Suspected TRALI
Report to blood center
Test patient for HLA and granulocyte antibodies/antigens
Test donor for HLA and granulocyte antibodies 62

63. Anaphylactic IgA deficient Track as special needs patient
Special order IgA deficient products
Washed RBCs and platelets may be given 63

64. Delayed Reactions Positive antibody screen New antibody
Anamnestic or primary response
Autocontrol/DAT may be + or -
Eluate if transfused < 2 weeks ago
Antigen type pre-transfusion sample and donor segments 64

65. Delayed Testing Antibody identification studies
Bilirubin may increase at 5 days
CBC may show decreased Hgb
Urinalysis may show hemoglobinuria 65

66. Abbreviated Investigation
Simple allergic
Few hives early in transfusion
Clerical check
Visual check
Omit repeat ABO and DAT 66

67. Reporting FDA Fatalities BPDR for manufacturing errors Supplier
Bacterially contaminated units
TRALI
Physician
All investigation reports
Includes delayed reaction reports 67

68. Questions? 68